Submitted June 9, 2008
Accepted January 3, 2009
Runx2 induces acute myeloid leukemia in cooperation with Cbf
-SMMHC in mice
Ya-Huei Kuo, Sayyed K Zaidi, Svetlana Gornostaeva, Toshihisa Komori, Gary S. Stein, and Lucio H. Castilla*
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA, United States
Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, United States
Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
* Corresponding author; email: lucio.castilla{at}umassmed.edu.
The core-binding factor (CBF) is a master regulator of developmental and differentiation programs, and CBF alterations are frequently associated with acute leukemia. The role of the CBF member RUNX2 in hematopoiesis is poorly understood. Genetic evidence suggests that deregulation of Runx2 may cause myeloid leukemia in mice expressing the fusion oncogene Cbfb-MYH11. In this study, we show that sustained expression of Runx2 modulates Cbf
-SMMHC mediated myeloid leukemia development. Expression of Runx2 factor is high in the hematopoietic stem cell compartment and decreases during myeloid differentiation. Sustained Runx2 expression hinders myeloid progenitor differentiation capacity, and represses expression of CBF targets Csf1R, Mpo, Cebpd, the cell cycle inhibitor Cdkn1a, and myeloid markers Cebpa and Gfi1. In addition, full length Runx2 cooperates with Cbf-SMMHC in leukemia development, in transplantation assays. Furthermore, we show that the nuclear-matrix targeting signal and runt-homology domain of Runx2 are essential for its leukemogenic activity. Conversely, Runx2 haplo-insufficiency delays the onset and reduces the incidence of AML. Together, these results indicate that Runx2 is expressed in the stem cell compartment, interferes with differentiation and represses CBF targets in the myeloid compartment, and modulates the leukemogenic function of Cbf-SMMHC in mouse leukemia.
